Serine proteases are an important class of enzymes which have a serine residue at the active site. Elastase is one such serine protease which is released from azurophilic granules of human polymorphonuclear leukocytes (PMN) and macrophages by inflammatory stimuli. Human leukocyte elastase (HLE) has been reported to be capable of degrading the connective tissue component elastin in addition to a number of other connective tissue substrates resulting in a variety of clinically important imflammatory diseases e.g. pulmonary emphysema, rheumatoid arthritis, spondylitis, psoriasis, osteoarthritis, chronic bronchitis, cystic fibrosis, and respiratory distress syndrome (RDS). Under normal conditions, the proteolytic activity of elastase in the extracellular environment is limited by the presence of excess of natural inhibitors like .alpha..sub.1 protease inhibitor (.alpha..sub.1 PI) and .alpha..sub.2 macroglobulin. Marked reduction in serum .alpha..sub.1 PI either genetic or due to oxidants, results in protease-antiprotease imbalance and thus leads to uncontrolled proteolysis of connective tissue, primarily of the lung and joints [J. Travis et al. Ann. Rev. Biochem., 52, 655 (1983)]. Pulmonary emphysema is a disease characterized by a progressive loss of lung elasticity and resulting in respiratory difficulty. This loss of lung elasticity is caused by progressive destruction of the structure of lung tissue by elastase released from leukocytes. Use of low molecular weight synthetic human leukocyte elastase (HLE) inhibitors would be an ideal therapeutic approach in controlling the various inflammatory conditions.
Cephem sulfones have been described as elastase inhibitors in various patents and publications. See, for example, U.S. Pat. No. 4, 547,371; EP patent nos. 267,723 and 337,704; AU patent nos. 80624/87 and 32762/89; J. Med. Chem., 33, 2513 (1990); J. Med. Chem., 33, 2522 (1990); J. Med. Chem., 33, 2529 (1990); J. Org. Chem., 54, 3907 (1989), Eur. J. Med. Chem., 24, 599 (1989); Am. Rev. Respir. Dis., 141, 672 (1990); J. Cell. Biochem., 39, 47 (1989); and Nature, 322, 192 (1986).